Background: For antibiotic treatment of Acute exacerbations of COPD (AECOPD) the National guidelines in Denmark recommend either first choice amoxicillin 750 mg TID (AMX) or amoxicillin with clavulanic acid 500 mg/125 mg TID (AMC). Addition of clavulanic acid offers a broader spectrum; opposite, AMX alone in a higher dose may offer more time above MIC. The aim of this study was to determine which of these regimens is associated with better outcome. Methods: The Danish Registry of COPD (DrCOPD), a nationwide outpatient COPD registry, was crosslinked with medication data and hospital contacts. The first prescription of AMX or AMC after inclusion in DrCOPD was used as exposure variable. Adjusted Cox proportional hazards models were used to analyze the risk of hospitalization or death (combined) within 30 days and other endpoints. Results: For the first treatment of AECOPD 12,915 received AMX, and 30,721 patients received AMC. AMX was associated with a decreased risk of pneumonia hospitalization or death (aHR 0.6, 95% CI 0.5–0.7; p < 0.0001) compared to AMC. Conclusion: In AECOPD, empirically adding clavulanic acid to amoxicillin is not associated with a better outcome; it seems safe for these patients to be treated with amoxicillin alone.